Abstract
The advent of click chemistry has had a profound impact on many fields and fueled a need for reliable reactions to expand the click chemistry toolkit. However, developing new systems to fulfill the click chemistry criteria remains highly desirable yet challenging. Here, we report the development of light-induced primary amines and o-nitrobenzyl alcohols cyclization (PANAC) as a photoclick reaction via primary amines as direct click handle, to rapid and modular functionalization of diverse small molecules and native biomolecules. With intrinsic advantages of temporal control, good biocompatibility, reliable chemoselectivity, excellent efficiency, readily accessible reactants, operational simplicity and mild conditions, the PANAC photoclick is robust for direct diversification of pharmaceuticals and biorelevant molecules, lysine-specific modifications of unprotected peptides and native proteins in vitro, temporal profiling of endogenous kinases and organelle-targeted labeling in living systems. This strategy provides a versatile platform for organic synthesis, bioconjugation, medicinal chemistry, chemical biology and materials science.
Highlights
The advent of click chemistry has had a profound impact on many fields and fueled a need for reliable reactions to expand the click chemistry toolkit
The spontaneous manner of these kinds of click reactions for native biomolecules remains challenging when applied into complex biological environments, since the reactions would initiate in extracellular environment or during the process approaching cellular targets once certain clickable functional groups are in proximity to each other[27,28]
With the unique mechanistic pathway[40] (Fig. 2a), the light-induced primary amines and o-nitrobenzyl alcohols cyclization (PANAC) conjugation presents excellent selectivity to primary amines groups, while being orthogonal to other common functional groups, including alcohols, phenols, carboxylic acids, secondary and tertiary amines, and nitrogen heterocycles in synthetic chemistry and conjugations (Fig. 3, 10–25). These results indicate that PANAC conjugation enabled modular functionalization of small molecules via primary amine group as direct click handle, providing rapid access to diverse molecules without laborious de novo chemical synthesis, which would find broad applications in organic synthesis[10], medicinal chemistry[46,47], and chemical biology[28]
Summary
The advent of click chemistry has had a profound impact on many fields and fueled a need for reliable reactions to expand the click chemistry toolkit. With intrinsic advantages of temporal control, good biocompatibility, reliable chemoselectivity, excellent efficiency, readily accessible reactants, operational simplicity and mild conditions, the PANAC photoclick is robust for direct diversification of pharmaceuticals and biorelevant molecules, lysine-specific modifications of unprotected peptides and native proteins in vitro, temporal profiling of endogenous kinases and organelle-targeted labeling in living systems. This strategy provides a versatile platform for organic synthesis, bioconjugation, medicinal chemistry, chemical biology and materials science. With intrinsic advantages of temporal control, reliable chemoselectivity, excellent efficiency, and readily accessible reactants, PANAC photoclick chemistry provides versatile platform for modular conjugation of multiple FM and primary amines, one of the most abundant functional groups as straightforward click handle, expanding the click chemistry toolkit
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